Japanese encephalitis - JE
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From Wikipedia, the free encyclopedia
| Japanese encephalitis | |
|---|---|
| Classification and external resources | |
| Specialty | Infectious disease |
| ICD-10 | A83.0 |
| ICD-9-CM | 062.0 |
| DiseasesDB | 7036 |
| eMedicine | med/3158 |
| MeSH | D004672 |
| Japanese encephalitis | |
|---|---|
| Virus classification | |
| Group: | Group IV ((+)ssRNA) |
| Family: | Flaviviridae |
| Genus: | Flavivirus |
| Species: | Japanese encephalitis virus |
Japanese encephalitis (Japanese: 日本脳炎, Nihon-nōen)— abbreviated JE, formerly known as Japanese B encephalitis to distinguish it from Economo's A encephalitis—is a disease caused by the mosquito-borne Japanese encephalitis virus (JEV).[1] The Japanese encephalitis virus (JEV) itself is a virus from the family Flaviviridae, part of the Japanese encephalitis serocomplex of 9 genetically and antigenically related viruses,[2] some which are particularly severe in horses, and four known to infect humans including West Nile virus.
Domestic pigs and wild birds (especially herons) are reservoirs of the virus; transmission to humans may cause severe symptoms. Amongst the most important vectors of this disease are the mosquitoes Culex tritaeniorhynchus and Culex vishnui. This disease is most prevalent in Southeast Asia and East Asia.
Signs and symptoms[edit]
Japanese encephalitis has an incubation period of 5 to 15 days and the vast majority of infections are asymptomatic: only 1 in 250 infections develop into encephalitis.
Severe rigors may mark the onset of this disease in humans. Fever, headache and malaise are other non-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs which develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions and a raised body temperature between 38–41 °C (100.4–105.8 °F). Mental retardation is usually developed.
Mortality of this disease varies but is generally much higher in children.[citation needed] Transplacental spread has been noted. Lifelong neurological defects such as deafness, emotional lability and hemiparesis may occur in those who have had central nervous system involvement. In known cases some effects also include nausea, headache, fever, vomiting and sometimes swelling of the testicles.[citation needed]
Increased microglial activation following Japanese Encephalitis infection has been found to influence the outcome of viral pathogenesis. Microglia are the resident immune cells of the central nervous system (CNS) and have a critical role in host defense against invading microorganisms. Activated microglia secrete cytokines, such as interleukin-1 (IL-1) andtumor necrosis factor alpha (TNF-α), which can cause toxic effects in the brain. Additionally, other soluble factors such as neurotoxins, excitatory neurotransmitters,prostaglandin, reactive oxygen, and nitrogen species are secreted by activated microglia.
In a murine model of JE, it was found that in the hippocampus and the striatum, the number of activated microglia was more than anywhere else in the brain closely followed by that in the thalamus. In the cortex, the number of activated microglia was significantly less when compared with other regions of the mouse brain. An overall induction of differential expression of proinflammatory cytokines and chemokines from different brain regions during a progressive Japanese Encephalitis infection was also observed.
Although the net effect of the proinflammatory mediators is to kill infectious organisms and infected cells as well as to stimulate the production of molecules that amplify the mounting response to damage, it is also evident that in a nonregenerating organ such as brain, a dysregulated innate immune response would be deleterious. In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage.[3]
In animals, key signs include infertility and abortion in pigs, neurological disease in horses and systemic signs including fever, lethargy and anorexia.[4]
Prevention[edit]
Main article: Japanese encephalitis vaccine
Infection with Japanese Encephalitis confers lifelong immunity. There are currently three vaccines available: SA14-14-2, IC51 (marketed in Australia and New Zealand as JESPECT and elsewhere as IXIARO) and ChimeriVax-JE (marketed as IMOJEV).[5] All current vaccines are based on the genotype III virus.
A formalin-inactivated mouse-brain derived vaccine was first produced in Japan in the 1930s and was validated for use in Taiwan in the 1960s and in Thailand in the 1980s. The widespread use of vaccine and urbanization has led to control of the disease in Japan, Korea, Taiwan and Singapore. The high cost of this vaccine, which is grown in live mice, means that poorer countries have not been able to afford to give it as part of a routine immunization program.[1]
The most common adverse effects are redness and pain at the injection site. Uncommonly, an urticarial reaction can develop about four days after injection. Vaccines produced from mouse brain have a risk of autoimmune neurological complications of around 1 per million vaccinations.[6] However where the vaccine is not produced in mouse brains but in vitro using cell culture there is little adverse effects compared to placebo, the main side effects are headache and myalgia.[7]
The neutralizing antibody persists in the circulation for at least two to three years, and perhaps longer.[8][9] The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are recommended every three years for people who remain at risk.[10] Furthermore, there is also no data available regarding the interchangeability of other JE vaccines and IXIARO and recommended those previously immunised with other JE vaccines receive Green Cross or JE-Vax or a primary course of IXIARO.
In September 2012 an Indian firm Biological E Limited has launched an Inactivated Cell culture derived vaccine based on SA 14-14-2 strain which was developed in a Technology transfer agreement with Intercell and is a thiomersal-free vaccine.[11][12]
Treatment[edit]
There is no specific treatment for Japanese encephalitis and treatment is supportive;[13] with assistance given for feeding, breathing or seizure control as required. Raisedintracranial pressure may be managed with mannitol.[14] There is no transmission from person to person and therefore patients do not need to be isolated.[citation needed]
A breakthrough in the field of Japanese encephalitis therapeutics is the identification of macrophage receptor involvement in the disease severity. A recent report of an Indian group demonstrates the involvement of monocyte and macrophage receptor CLEC5A in severe inflammatory response in Japanese Encephalitis infection of the brain. Thistranscriptomic study provides a hypothesis of neuroinflammation and a new lead in development of appropriate therapeutic against Japanese encephalitis.[15][16]
Epidemiology[edit]
Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, with up to 70,000 cases reported annually.[17] Case-fatality rates range from 0.3% to 60% and depend on the population and age. Rare outbreaks in U.S. territories in the Western Pacific have also occurred. Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas.
Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, Republic of Korea, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, andMalaysia. Japanese encephalitis has been reported on the Torres Strait Islands and two fatal cases were reported in mainland northern Australia in 1998. There were reported cases in Kachin State, Myanmar in 2013. The spread of the virus in Australia is of particular concern to Australian health officials due to the unplanned introduction of Culex gelidus, a potential vector of the virus, from Asia. However, the current presence on mainland Australia is minimal.
Human, cattle and horses are dead-end hosts as the disease manifests as fatal encephalitis. Swine acts as an amplifying host and has a very important role in the epidemiology of the disease. Infection in swine is asymptomatic, except in pregnant sows, when abortion and fetal abnormalities are common sequelae. The most important vector is Culex tritaeniorhynchus, which feeds on cattle in preference to humans. It has been proposed that moving swine away from human habitation can divert the mosquito away from humans and swine. The natural hosts of the Japanese encephalitis virus are birds, not humans, and many believe the virus will therefore never be completely eliminated.[18] In November 2011, the Japanese encephalitis virus was reported in Culex bitaeniorhynchus in the Republic of Korea.[19]
Recently whole genome microarray research of neurons infected with the Japanese Encephalitis virus has shown that neurons play an important role in their own defense against Japanese Encephalitis infection. Although this challenges the long-held belief that neurons are immunologically quiescent, an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese Encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.[20]
A number of drugs have been investigated to either reduce viral replication or provide neuroprotection in cell lines or studies upon mice. None are currently advocated in treating human patients.
- The use of rosmarinic acid,[21] arctigenin,[22] and oligosaccharides with degree of polymerization 6 from Gracilaria sp. or Monostroma nitidum[23] have been shown to be effective in a mouse model of Japanese encephalitis.
- Curcumin has been shown to impart neuroprotection against Japanese Encephalitis infection in an in vitro study. Curcumin possibly acts by decreasing cellular reactive oxygen species level, restoration of cellular membrane integrity, decreasing pro-apoptotic signaling molecules, and modulating cellular levels of stress-related proteins. It has also been shown that the production of infective viral particles from previously infectedneuroblastoma cells are reduced, which is achieved by the inhibition of ubiquitin-proteasome system.[24]
- Minocycline in mice resulted in marked decreases in the levels of several markers, viral titer, and the level of proinflammatory mediators[25] and also prevents blood brain barrier damage.[26]
Evolution[edit]
The virus appears to have originated from its ancestral virus in the mid-1500s in the Indonesia-Malaysia region and evolved there into five different genotypes and spread across Asia.[27] The mean evolutionary rate has been estimated to be 4.35×10−4 (range: 3.4906×10−4 to 5.303×10−4) nucleotide substitutions per site per year.
Virology[edit]
The causative agent for Japanese encephalitis virus is an enveloped virus of the genus flavivirus and is closely related to the West Nile virus and the St. Louis encephalitis virus. The positive sense single-stranded RNA genome is packaged in the capsid which is formed by the capsid protein. The outer envelope is formed by envelope protein and is the protective antigen. It aids in entry of the virus into the inside of the cell. The genome also encodes several nonstructural proteins (NS1, NS2a, NS2b, NS3, N4a, NS4b, NS5). NS1 is produced as secretory form also. NS3 is a putative helicase, and NS5 is the viral polymerase. It has been noted that Japanese encephalitis infects the lumen of theendoplasmic reticulum (ER)[28][29] and rapidly accumulates substantial amounts of viral proteins for the Japanese Encephalitis.
Japanese encephalitis is diagnosed by detection of antibodies in serum and cerebrospinal fluid by IgM capture ELISA.[30]
Based on the envelope gene, there are five genotypes (I–V). The Muar strain, isolated from a patient in Malaya in 1952, is the prototype strain of genotype V. Genotype IV appears to be the ancestral strain, and the virus appears to have evolved in the Indonesian–Malayasian region. The first clinical reports date from 1870, but the virus appears to have evolved in the mid-16th century..
Over sixty complete genomes of this virus had been sequenced by 2010.
Japanese encephalitis
Key facts
- Japanese encephalitis (JE) is a flavivirus related to dengue, yellow fever and West Nile viruses, and is spread by mosquitoes.
- JE is the main cause of viral encephalitis in many countries of Asia with nearly 68 000 clinical cases every year.
- Although symptomatic JE is rare, the case-fatality rate among those with encephalitis can be as high as 30%. Permanent neurologic or psychiatric sequelae can occur in 30%–50% of those with encephalitis.
- 24 countries in the WHO South-East Asia and Western Pacific regions have endemic JE transmission, exposing more than 3 billion people to risks of infection.
- There is no cure for the disease. Treatment is focused on relieving severe clinical signs and supporting the patient to overcome the infection.
- Safe and effective vaccines are available to prevent JE. WHO recommends JE vaccination in all regions where the disease is a recognised public health problem.
Japanese encephalitis (JE) is the most important cause of viral encephalitis in Asia. It is a mosquito-borne flavivirus, meaning it is related to dengue, yellow fever and West Nile viruses. The first case of JE was documented in 1871 in Japan.
The annual incidence of clinical disease varies both across and within countries, ranging from <10 to="">100 per 100 000 population. A recent literature review estimates nearly 68 000 clinical cases of JE globally each year, with up to 20 400 deaths due to JE (Bulletin of WHO, October 2011). JE primarily affects children. Most adults in endemic countries have natural immunity after childhood infection, but individuals of any age may be affected.
Signs and symptoms
Most JE virus infections are mild (fever and headache) or without apparent symptoms, but approximately 1 in 250 infections results in severe disease characterized by rapid onset of high fever, headache, neck stiffness, disorientation, coma, seizures, spastic paralysis and death. The case-fatality rate can be as high as 30% among those with disease symptoms.
Of those who survive, 20%–30% suffer permanent intellectual, behavioural or neurological problems such as paralysis, recurrent seizures or the inability to speak.
Transmission
24 countries in the WHO South-East Asia and Western Pacific regions have JE transmission risk, which includes more than 3 billion people.
JE is transmitted to humans through bites from infected mosquitoes of the Culexspecies (mainly Culex tritaeniorhynchus). Humans, once infected, do not develop sufficient viraemia to infect feeding mosquitoes. The virus exists in a transmission cycle between mosquitoes, pigs and/or water birds (enzootic cycle). The disease is predominantly found in rural and periurban settings, where humans live in closer proximity to these vertebrate hosts.
In most temperate areas of Asia, the Japanese Encephalitis Virus (JEV) is transmitted mainly during the warm season, when large epidemics can occur. In the tropics and subtropics, transmission can occur year-round but often intensifies during the rainy season and pre-harvest period in rice-cultivating regions.
Diagnosis
Individuals who live in or have travelled to a JE-endemic area and experience encephalitis are considered a suspected JE case. To confirm JE infection and to rule out other causes of encephalitis requires a laboratory testing of serum or, preferentially, cerebrospinal fluid.
Surveillance of the disease is mostly syndromic for acute encephalitis. Confirmatory laboratory testing is often conducted in dedicated sentinel sites, and efforts are undertaken to expand laboratory-based surveillance. Case-based surveillance is established in countries that effectively control JE through vaccination.
Treatment
There is no antiviral treatment for patients with JE. Treatment is supportive to relieve symptoms and stabilize the patient. Clinical care guidelines have been developed by PATH.
Prevention and control
Safe and effective JE vaccines are available to prevent disease. WHO recommends having strong prevention and control activities, including JE immunization in all regions where the disease is a recognized public health problem, along with strengthening surveillance and reporting mechanisms. Other control measures such as mosquito control or amplifying pig control have shown to be less reliable.
There are four main types of JE vaccines currently in use: inactivated mouse brain-based vaccines, inactivated cell-based vaccines, live attenuated vaccines, and live chimeric vaccines. Traditionally, the most widely used vaccine was a purified inactivated product made from either Nakayama or Beijing strains propagated in mouse brain tissue. It is still produced and used in several countries.
Over the past years, the live attenuated SA14-14-2 vaccine manufactured in China has become the most widely used vaccine in endemic countries, and it was prequalified by WHO in October 2013. Cell-culture based inactivated vaccines have also been licensed (and one product WHO prequalified), as has a live, recombinant product based on the yellow fever vaccine strain. In November 2013, GAVI opened a funding window to support JE vaccination campaigns in eligible countries.
All travellers to Japanese encephalitis-endemic areas should take precautions to avoid mosquito bites to reduce the risk for JE. Personal preventive measures include the use of repellents, long-sleeved clothes, coils and vaporizers.
Disease outbreaks
Major outbreaks of JE occur every 2-15 years. JE transmission intensifies during the rainy season, during which vector populations increase. However, there has not yet been evidence of increased JE transmission following major floods or tsunamis. The spread of JE in new areas has been correlated with agricultural development and intensive rice cultivation supported by irrigation programmes.
WHO responds to JE by:
- providing global recommendations for JE control, including the use of vaccines. WHO recommends JE immunization in all regions where the disease is a recognized public health problem and supports implementation.
- providing technical support for JE surveillance, JE vaccine introduction and large-scale JE vaccination campaigns.
For more information contact:
WHO Media centre
Telephone: +41 22 791 2222
E-mail: mediainquiries@who.int
Telephone: +41 22 791 2222
E-mail: mediainquiries@who.int
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